Intrathecal glycine for pain and dystonia in complex regional pain syndrome

Since glycinergic neurotransmission plays an important inhibitory role in the processing of sensory and motor information, intrathecal glycine (ITG) administration may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Aims of the current study, which is the first report on ITG in humans, were to evaluate its safety and efficacy. ITG treatment during 4 weeks was studied in CRPS patients with dystonia in the period before they received intrathecal baclofen treatment. Twenty patients were assessed and after exclusion of one patient, the remaining 19 patients were randomized in a double-blind placebo-controlled crossover study. Safety was assessed by clinical evaluation, blood examinations and electrocardiograms. Efficacy measures involved pain (numeric rating scale, McGill pain questionnaire), movement disorders (Burke–Fahn–Marsden dystonia rating scale, unified myoclonus rating scale, tremor research group rating scale), activity (Radboud skills questionnaire, walking ability questionnaire), and a clinical global impression (CGI) and patient’s global impression score (PGI). Treatment-emergent adverse events were generally mild to moderate and not different from placebo treatment. During ITG treatment growth hormone levels were slightly increased. Although there was a trend to worsening on the CGI and PGI during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. ITG given over 4 weeks was ineffective for pain or dystonia in CRPS. Although no serious adverse events occurred, further studies are required to rule out potential neurotoxicity of ITG.     

CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief

Seventeen patients with advanced cancer pain, treated with chronic epidural morphine, were studied. Minimum plasma and CSF morphine concentrations (Css_min) were determined at pharmacokinetic steady state. A linear relationship was found between epidural morphine dose and concentrations obtained in plasma (r = 0.92) as well as CSF (r = 0.90). The line for best fit was much steeper for CSF than for plasma. The CSF/plasma concentration gradient of morphine at Css_min was 132 ± 31 (mean ± S.E.M.). Large interindividual variations of morphine concentrations in CSF were found. It is suggested that the variations are due to substantial differences in transdural morphine diffusion between individuals. No correlation was found between pain relief, evaluated with a visual analog scale, and CSF morphine concentrations at pharmacokinetic steady state, when calculated in 9 patients. Mean duration of treatment was 104 days (range 14–366) and the daily dose was increased from 18 ± 2 to 87 ± 31 mg/day (mean ± S.E.M.). A total of 39 epidural catheters were inserted in 14 patients. The catheters were patent for 2–223 days with a mean of 38 days. When re-examined later during treatment, 2 out of 8 patients demonstrated decreased CSF morphine concentrations in spite of increased doses given. One patient with extremely high dose demand is reported on separately and data supporting the concept of a combined spinal and systemic brain morphine effect in such cases are presented. Side effects were not a major problem but the possibility of infectious complications should be considered during chronic epidural morphine therapy.     

A randomized study on oral administration of morphine and methadone in the treatment of cancer pain

Over a period of 14 days, 54 patients with incurable chronic cancet pain were observed: 27 were randomized for treatment with morphine per os and 27 with methadone per os. Data regarding daily dosage, analgesic effects, hours of sleep, hours standing, performance status (PS) and side effects were collected during both treatments. The results show overlapping analgesic efficacy and side effects for both drugs, and confirm the hypothesis that lower doses of methadone are required than morphine. In the treatment with methadone, the initial average dose was 18 mg, and this dose was maintained throughout the entire period, whereas the initial average daily dose of morphine was 72.74 mg (±39.25), and the final average daily dose was 119.40 mg (±79.1). The findings in this study show that methadone is a valid alternative to morphine in cancer pain treatment even though, as a result of its pharmaceutical charcteristics, it requires a differnt titration for the patient.     

癌性疼痛患者应用吗啡的影响因素及分析

目的 探讨癌性疼痛患者使用吗啡的影响因素,为临床护士实施护理措施提供帮助.方法 2010年4月1日-2010年10月31日对收住上海中医药大学附属普陀医院肿瘤科未服用吗啡的癌性疼痛患者87例进行调查,内容包括一般情况和影响吗啡应用的因素.结果 影响吗啡应用的主要因素:63.2%患者担心吗啡成瘾性;60.9%患者担心吗啡耐药性、剂量会增加;57.4%患者担心吗啡的不良反应难以忍受;44.8%患者认为疼痛一定会有,无法治疗,只能忍受;34.5%患者认为病情还未发展到需服用吗啡的程度;28.7%患者担心过早使用吗啡,今后疼痛加重则无法控制疼痛;21.8%患者担心吗啡价格昂贵、负担不起等.结论 根据影响患者吗啡应用的主要因素,制订适合患者需求的健康教育,提高癌性疼痛患者正确应用吗啡的认知状态,有助于癌症患者正确使用吗啡,减少不良反应的发生,提高癌症患者的生活质量.     

Intrathecal infusional analgesia for nonmalignant pain: Analgesic efficacy of intrathecal opioid with or without bupivacaine

We report on the analgesic efficacy of intrathecal infusions ofopioids alone or in combination with bupivacaine in 16 nonmalignant pain patients with implanted pumps. Three patients had nociceplive pain, five had neuropathic pain, and 8 had mixed pain syndromes. Infusional therapy was delivered over a combined monthly total of 445 mo of therapy (mean, 27.8 mo). Dose requirements appeared to be stable with a mean dose increase of 0.26 mg/mo. Bupivacaine was added to the opioid to enhance pain control in 13 patients who received combination therapy for an average of 11.7 molpatient. Thirteen patients (81 %) reported good to excellent results with opioid alone or opioid combined with bupivacaine. The addition of bupivacaine improved analgesia in two of three patients with nociceptive pain (66.7%), compared to eight often patients with a pure or mixed neuropathic component to their pain (80%). We conclude that intrathecal opioids alone or in combination with bupivacaine are efficacious for the treatment of nonmalignant pain states and are relatively free of significant side effects or tolerance.     

蛛网膜下腔给予不同剂量的吗啡用于术后镇痛

目的:研究蛛网膜下腔给予多大剂量的吗啡用于术后镇痛的疗效和安全性。方法:70例进行全髋置换术病人,术后随机双盲蛛网膜下腔给予0．2mg或者0．5mg吗啡用于镇痛。在术后第1个24 h有多少病人需要曲马多进行术后镇痛补救,以及曲马多总共消耗剂量和不良反应发生率。结果:0．2mg和0．5 mg剂量组术后的第1个24 h需要追加剂量病人数分别为,16(48％)和28(85％)(P=0．003);0．2 mg和0．5 mg组病人在术后需要追加曲马多的剂量分别为45．4± 24．6 mg和85．5±34．3 mg(P=0．002);在两个组中不良反应的发生率基本相似。结论:蛛网膜下腔给与0．5 mg吗啡可以产生较0．2 mg更明显的术后镇痛效果,同时不增加不良反应的发生率。     

Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects.

Methadone is used as an alternative opioid when first line opioids fail to provide adequate pain control. Highly variable morphine:methadone dose ratios make switching challenging and little is known about the pharmacokinetics of long lasting methadone treatment for pain. Twelve patients treated with morphine for chronic non-malignant pain were switched to methadone. Seven of these patients continued with methadone throughout the nine months study period and only minor dose adjustments were performed. Serum concentrations of morphine, methadone and their metabolites were measured at baseline, day one and two, after dose titration and one week, five weeks, three months and nine months after the end of dose titration. Serum concentrations of methadone and its metabolite EDDP did not change significantly from the end of dose titration and during the nine months (repeated measures ANOVA: p=0.88 and p=0.06). Very low correlation between dose ratios and serum concentration ratios between morphine and methadone was observed. Large interindividual differences in serum concentrations and metabolism were observed. Our findings contradict that autoinduction of methadone metabolism takes place during long term treatment and supports that a 3-day opioid switch from morphine to methadone followed by a one week titration seems pharmacologically sound.     

Successful use of ketamine for intractable cancer pain

Goals and work Despite medical awareness, intractable pain is a serious problem in cancer and occurs in up to 2% of advanced cancer patients. However, few data are available concerning the optimal treatment of such patients. The emergence of intractable pain may notably be due to the activation of N-methyl-D-aspartate (NMDA) receptors located in the central nervous system. NMDA antagonists might thus be an interesting approach in such pain syndromes.Patients and methods Twelve patients with intractable cancer pain received a test dose of 5–10 mg of ketamine, a strong NMDA antagonist, in order to determine their response and tolerance to the drug. Continuous intravenous infusions of ketamine associated with morphine were then administered.Main results The acute test dose was successful in all cases (VAS <3/10 after 5 min). The prolonged use of ketamine allowed us to reduce the total daily dose of morphine required (range: 200–1,200 mg) by 50% and allowed eight patients to go home with a portable pump with morphine and ketamine during a relatively long period of time (range: 7–350 days, median: 58 days). Side effects were moderate (dizziness) and they were limited to the test phase.Conclusion Our data suggest the importance of NMDA receptors in the genesis of chronic cancer pain and indicate that NMDA antagonists should be further studied for the management of cancer pain and, in particular, intractable pain.     

Sustained‐release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management

Purpose: The aim of this study was to compare the analgesic and adverse effects, doses, as well as cost of opioid drugs, supportive drug therapy and other analgesic drugs in patients treated with oral sustained‐release morphine, transdermal fentanyl, and oral methadone. Patients and methods: One hundred and eight cancer patients, no longer responsive to opioids for moderate pain, were selected to randomly receive initial daily doses of 60mg of oral sustained‐release morphine, 15mg of oral methadone, or 0.6mg (25μg/h) of transdermal fentanyl. Oral morphine was used as breakthrough pain medication during opioid titration. Opioid doses, pain intensity, adverse effects, symptomatic drugs, were recorded at week intervals for 4weeks. Costs of opioid therapy, supportive drugs, and other analgesic drugs were also evaluated. Results: Seventy patients completed the 4weeks period of study. Five, five, and four patients, treated with oral morphine, transdermal fentanyl, and oral methadone, respectively, required opioid switching. No differences in pain and symptom intensity were observed. Opioid escalation index was significantly lower in patients receiving methadone (p<0.0001), although requiring up and down changes in doses. At the doses used, methadone was significantly less expensive (p<0.0001), while the use and costs of supportive drugs and other analgesics were similar in the three groups. No relevant differences in adverse effects were observed among the groups during either the titration phase and chronic treatment. Conclusion: All the three opioids used as first‐line therapy were effective, well tolerated, and required similar amounts of symptomatic drugs or co‐analgesics. Methadone was significantly less expensive, but required more changes, up and down, of the doses, suggesting that dose titration of this drug requires major clinical expertise.     

Peroperative ketamine and morphine for postoperative pain control after lumbar disk surgery.

BACKGROUND: Ketamine, a N-methyl-D-aspartate receptor antagonist, may reduce postoperative opioid demand and improve postoperative analgesia. METHODS: Sixty-nine patients scheduled for lumbar disk surgery under general anaesthesia were enrolled in a randomised, double-blind study comparing three analgesic combinations that were started before surgical incision: morphine 0.1 mg kg(-1) alone (group M; n=23); ketamine 0.15 mg kg(-1) alone (group K; n=22); and a combination of morphine 0.1 mg kg(-1) with ketamine 0.15 mg kg(-1) (group KM; n=23). Postoperatively patient-controlled analgesia was provided with intravenous morphine. Morphine consumption was assessed during 24 H, and pain scores were measured using a visual analogue scale (VAS) at rest and on mobilisation, during the first two postoperative days. RESULTS: In group KM, less i.v. morphine was administered in the post anaesthesia care unit than in group M (median [range]: 0mg [0-2] vs. 7 mg [6-9], P=0.009). Cumulative 24 H morphine consumption was reduced by 57% in group KM vs. group M, and by 48% in group KM vs. group K. Postoperative VAS scores were lower in group KM vs. groups K and M. Maximal VAS score on mobilization was reduced in group KM compared to groups K and M (38 mm [35-45] vs. 52 mm [48-59] and vs. 59 mm [55-64], in groups KM, K and M, respectively, P=0.05 and P=0.002). The incidence of postoperative nausea and vomiting was decreased in group KM compared to group M (21.7% vs. 43.5%, P=0.001). CONCLUSION: Ketamine small-dose, combined with morphine improves postoperative analgesia and reduces opioid-related side effects in lumbar disk surgery.     

Intrathecal baclofen as adjuvant therapy to enhance the effect of spinal cord stimulation in neuropathic pain: a pilot study.

Only about 60-70% of well selected patients with neuropathic pain syndromes of peripheral origin enjoy sufficient pain relief with spinal cord stimulation (SCS). Since recent animal experiments have demonstrated that the GABA-B receptor is pivotal in the effect of SCS on certain neuropathic symptoms, the use of baclofen as an adjunct to stimulation emerged as an option in patients not responding satisfactorily to SCS. Forty-eight patients with neuropathic pain of peripheral origin responding poorly to SCS were enrolled in a study with intrathecal baclofen; in a few cases adenosine was also tried. Twenty patients reported significant pain reduction at bolus trials and were offered implantation of a drug pump. Seven patients subsequently had pumps implanted together with SCS and four had pumps alone. Three patients had only peroral baclofen therapy as an adjunct to SCS. The 14 patients continuing with baclofen therapy as an adjunct to SCS, or alone, were followed for an average of 35 months after pump implant. The group with SCS+pump n=5; 2 explanted) reported an average decrease of pain ratings from VAS 82 to 33. The group with i.t. baclofen only had a pain decrease from VAS 63 to 33, while the three patients with peroral baclofen+SCS had less benefit from drug therapy. Adjunctive drug therapy for patients with unsatisfactory pain relief by SCS may offer a possibility to enhance pain alleviation.     

Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain.

BACKGROUND: In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled. METHODS: Assessments for pain, sedation and other morphine induced side effects were made several times for 19 cancer patients treated with changing doses of oral sustained release (SR) morphine and twice for 17 non-cancer patients treated with stable doses of SR morphine. Blood samples were obtained simultaneously and analysed for contents of morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC). RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (r = 0.469, p < 0.01), plasma M-6-G (r = 0.677, p < 0.01), and plasma M-3-G ((r = 0.827, p < 0.01), in the cancer patient group, but only between the daily dose of SR morphine and plasma M-3-G (0.662, p < 0.01) and plasma M-6-G (0.571, p < 0.01) in the non-cancer patient group. Normalised M-3-G/M and M-6-G/M ratios for the cancer patient group were independent of duration of treatment and daily dose of SR morphine. Likewise in the non-cancer patient group duration of treatment did not influence the metabolite ratios. Correlations between pain score and plasma morphine, M-6-G and M-6-G/M were weak in the cancer patient as well as in the non-cancer patient group making it impossible to draw any conclusion regarding the potential contributory analgesic effect of M-6-G. Dryness of the mouth was the most frequent adverse effect reported in the non-cancer as well as the cancer patient group. In the latter group patients complaining of dryness of the mouth had significantly higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. This difference persisted (or was close to significance) when excluding patients receiving antidepressants. CONCLUSION: In the cancer patient group neither dose nor treatment period seems to influence morphine glucuronidation. Likewise in the non-cancer patient group receiving stable doses of morphine duration of treatment does not seem to influence morphine glucuronidation. Dryness of the mouth was positively correlated to high plasma concentrations of morphine and M-6-G.     

The opiate-sparing effect of dipyrone in post-operative pain therapy with morphine using a patient-controlled analgesic system

Objective To determine whether dipyrone has an opiate-sparing effect in post-operative pain therapy compared with placebo during patient-controlled morphine therapy (PCA) and to compare the effects on analgesia and respiratory and coagulation parameters.Design Randomized, observer-blind, parallel-group, placebo-controlled study.Setting Surgical intensive care unit of a university hospital.Patients 106 adult patients who were to undergo abdominal or urological surgery under 90-min standardized inhalational anaesthesia were entered and 103 were included in the efficacy analysis (53 on dipyrone, 50 on placbo).Interventions Preprogrammed PCA (0.03 mg morphine/kg per bolus) with either dipyrone (initially 2.0 g i.v. and 1.0 g/2 ml i.v. at 4, 8 and 16 h) or placebo (saline).Measurements and results Cumulative morphine consumption was calculated automatically during PCA. Pain intensity and pain relief and the investigator's global assessments of efficacy and tolerability were recorded on five-point verbal rating scales. Vital signs, standard laboratory parameters, respiratory rate, partial pressure of carbon dioxide (PCO₂) and of oxygen, partial thromboplastin time (PTT) and Quick values were recorded. Total consumption of opiates in the dipyrone group (median 31.6 mg) was significantly less (p=0.00015) than in the placebo group (median 50.3 mg), while pain relief (area under the curve) AUC was the same for both PCA+dipyrone (median 4.1) and PCA+placebo (median 3.9). Global assessment of efficacy was good to excellent in more than 90% of cases in both groups. Vital signs, respiratory rate, PCO₂, PTT and Quick did not differ between groups. Adverse events were mainly nausea and/or vomiting (dipyrone,n=4; placebo,n=1); 1 patient in the placebo group had bradycardia. Three serious adverse events were unrelated to study medication. In 1 patient, the PCA programme malfunctioned and had to be changed.Conclusions concomitant administration of dipyrone with on-demand morphine (PCA) reduces opiate consumption while maintaining post-operative pain relief with a low incidence of side-effects.Sponsor: Hoechst Marion Roussel, Frankfurt/Main, Germany     

Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: a pilot study

Goals of work Inadequate analgesia and/or unmanageable adverse events frequently result in the need to rotate patients with cancer pain to a different opioid. The availability of a novel oral extended-release (ER) formulation of oxymorphone provides clinicians with another treatment option. In this study, we assessed the analgesic effectiveness and safety of the new oral ER formulation of oxymorphone following treatment with controlled-release (CR) morphine sulfate or oxycodone.Patients and methods Adults with moderate to severe cancer pain were stabilized for 3 days on morphine CR or oxycodone CR, and then treated for 7 days at their stabilized dose. Drug selection was based upon patients previous use or investigator preference. Patients were then crossed over for 7 days of treatment at an estimated equianalgesic dosage of oxymorphone ER. Pain was assessed using a visual analog scale, and adverse events were recorded.Main results A total of 86 patients entered open-label treatment. Of 34 patients assigned to morphine CR and 52 assigned to oxycodone CR, 21 (61.8%) and 42 (80.8%) completed stabilization and began treatment with oxymorphone ER, respectively; 59 of 63 (93.7%) completed treatment with oxymorphone. There were no significant differences in daily pain intensity scores between oxymorphone ER and comparators (paired t -test). Rescue medication use, expressed as the percent of the daily dose of scheduled opioid, was greater during morphine CR treatment than after crossover to oxymorphone ER (25.2% vs 13.3%; P <0.05, Wilcoxons test). The tolerability/safety profiles (e.g., nausea, drowsiness, somnolence) were similar for all opioids.Conclusions Cancer patients stabilized on morphine CR or oxycodone CR were safely and rapidly converted to a lower milligram dose of oxymorphone ER that provided adequate pain relief with comparable tolerability. These results justify additional trials with oxymorphone ER.This work was supported by Endo Pharmaceuticals Inc., Chadds Ford, PA, and Penwest Pharmaceuticals Co., Danbury, CT.     

奥施康定片治疗中、重度癌痛的临床观察与护理

目的观察奥施康定片对中、重度癌痛患者的止痛效果及不良反应。方法106例中、重度癌痛患者口服奥施康定片,记录治疗前后的疼痛强度、生活质量评分及不良反应。结果CR PR 102例,MR 3例,NR 1例。不良反应有便秘、恶心呕吐、嗜睡、头晕乏力等,发生率低。结论奥施康定片能有效控制癌性疼痛,改善生活质量,且不良反应轻微,发生率低。     

Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain

Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid-induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low-back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed.     

吗啡静脉自控镇痛用于晚期癌性疼痛效果观察

目的总结吗啡静脉自控镇痛(PCIA)在晚期癌性疼痛治疗中应用经验。方法40例Ⅳ期中到重度癌性疼痛患者静脉输入吗啡治疗,采用视觉模拟评分法(VAS)或0~10数字疼痛强度分级法(NRS)对疼痛程度进行评估,使用生活质量(QOL)评价,观察记录不良反应。结果大部分患者在PCIA镇痛期间,疼痛明显缓解,但随着时间的延长,吗啡剂量的增大,平均初始剂量为(70.4±21.7)mg/d,治疗终点的剂量为(286.3±95.5)mg/d,平均治疗时间(38.3±12.1)天。生活质量均有一定程度的改善,不良反应较轻。结论PCIA可安全用于晚期癌性疼痛治疗,具有使用方便、疗效确定、不良反应轻等优点。     

Attitudes of Swiss physicians in prescribing opiates for cancer pain

Following clinical observations showing that opiates are sometimes not consistently administered for chronic cancer pain, a survey was conducted among 1200 physicians in the German-speaking part of Switzerland. Their opium-prescribing habits were assessed by means of a postal questionnaire. The results indicate that, among the majority of physicians completing the questionnaire, established guidelines and basic principles of pain control with opiates in cancer patients are largely understood. Oral morphine is chosen by 89% to initiate treatment of chronic cancer pain, and the correct use of slow-release morphine is known to 87% of the responding physicians. Unfortunately, an important minority of physicians does not follow established guidelines in the treatment of cancer pain, and up to 20% still feel that the danger of addiction, respiratory depression and other side-effects are important reasons for withholding opiates in this patients population. The results and their implications are discussed and compared with the current literature on cancer pain management.     

Modification of attentional biases in chronic pain patients: a preliminary study

Research suggests that chronic pain patients demonstrate cognitive biases towards pain-related information and that such biases predict patient functioning. This study examined the degree to which a successful cognitive-behavioural program was able to reduce the observed attentional bias towards sensory pain words. Forty-two patients with chronic pain conditions for more than three months were recruited prior to commencing a cognitive-behavioural pain management program. Participants were assessed before the program, after the program and at one-month follow-up. Results confirmed that chronic pain patients exhibited biased attention towards sensory pain-related words at pre-treatment. These biases were still evident at post-treatment, but were no longer statistically significant at follow-up. Multiple regression analyses indicated that the changes in attentional bias towards sensory words between post-treatment and follow-up were predicted by pre- to post-treatment changes in fear of movement (Tampa Scale for Kinesiophobia) but not other relevant variables, such fear of pain or anxiety sensitivity. These results demonstrate that successful cognitive-behavioural treatments can reduce selective attention, thought to be indicative of hypervigilance towards pain. Moreover, these biases appear to be changed by reducing the fear associated with movement. Theoretically, these results provide support for the fear of (re)injury model of pain. Clinically, this study supports the contention that fear of (re)injury and movement is an appropriate target of pain management and that reducing these fears causes patients to attend less to pain-related stimuli.     

Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain

Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.